Browsing by Subject "solid dispersions"
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Item Investigating the Interactions of Polymeric Excipients with Poorly Water-Soluble Drugs as Means for Pharmaceuticals Bioavailability Enhancement(2019-02) Purchel, AnatoliiOral administration is the most preferable route of drug delivery, especially during prolonged therapy of chronic diseases. Unfortunately, many effective pharmaceuticals are poorly water-soluble, which leads to decreased bioavailability and shelf life. One of the ways to improve drug solubility and efficacy is to prepare an amorphous solid dispersion (ASD) with a polymer excipient. It is important that the polymer matrix of an ASD will stabilize the drug in the amorphous state and maintain its supersaturated concentration long enough in the dissolution media. Some of the commercial polymeric systems have shown a positive impact on drug dissolution, but most of them are difficult to characterize due to high polydispersity and system complexity. Most of the available excipients that improve dissolution of poorly water-soluble drugs tend to form nano-aggregates in the solution. Thus, in order to understand structure-property relationships better, various polymers were explored, which self-assemble into micelle-like structures or exist as free polymer chains in the solution, as excipients for dissolution of a model drugs such as probucol and phenytoin. Reversible addition-fragmentation chain transfer (RAFT) polymerization was used as a controlled polymerization technique to obtain well-defined polymers of polystyrene, poly(acrylic acid), N-isopropylamide, 4-vinylpyridine, N,N-dimethylacrylmide, and trehalose-derived monomers. The polymers were characterized by nuclear magnetic resonance (NMR) spectroscopy and size exclusion chromatography (SEC). The effects of nano-aggregation in ASDs, polymer charge, H-bonding and hydrophobic interactions on drug dissolution were determined. Caco-2 cell permeability assay was applied to determine cell permeability of drugs in some of the obtained formulations.Item The Role Of Molecular Mobility And Hydrogen Bonding Interactions On The Physical Stability Of Amorphous Pharmaceuticals(2014-09) Kothari, KhushbooThe physical instability of amorphous pharmaceuticals and our inability to reliably predict their crystallization propensity is a major impediment to their use in solid oral dosage forms. The central goal of this thesis work is to gain a fundamental insight into the roles of (i) specific molecular mobility (global or local) on the observed physical instability (crystallization) in the supercooled as well as glassy states of amorphous pharmaceuticals and (ii) the influence of hydrogen bonding on molecular mobility and thereby the physical stability. Our ultimate objective is to be able to use molecular mobility as a predictor of drug crystallization from complex multi-component solid dispersions. The different modes of molecular motions were comprehensively characterized using broadband dielectric spectroscopy (BDS). Since, BDS is traditionally conducted with film samples, we first validated the use of powder samples for measuring molecular mobility. Crystallization kinetics was monitored by powder X-ray diffractometry using either a laboratory or a synchrotron X-ray source. Physical instability, both above and below Tg in our model systems (griseofulvin, nifedipine and nifedipine-PVP dispersion), increased with a decrease in structural relaxation time. Next, a causal relationship between hydrogen bonding interactions and molecular mobility was established. The higher physical stability in felodipine as compared to nifedipine was attributed to the reduced molecular mobility brought about by the stronger and more extensive hydrogen bonding interactions in the former. In solid dispersions of nifedipine with each PVP, HPMCAS and PAA, the drug-polymer interactions, by modulating molecular mobility, influenced the drug crystallization kinetics. The strength of drug-polymer hydrogen bonding, the structural relaxation time and the crystallization kinetics were rank ordered as: PVP > HPMCAS > PAA. Finally a model derived from the relationship between diffusion and relaxation time was used to predict drug crystallization from solid dispersions. Molecular mobility proved to be an effective predictor of drug crystallization in nifedipine solid dispersions.Item Tunable Polymers as Specialized Excipients for Oral Drug Delivery(2016-08) Ting, JeffreyFor the continued advancement of modern pills and tablets in oral drug administration, spray–dried dispersions (solid–solid mixtures of amorphous drugs and polymers) have the potential to elevate poor drug solubility by orders of magnitude through drug supersaturation, thereby enhancing the therapeutic potency, oral bioavailability, and safety of accessible, lifesaving medicines worldwide. However, drug formulation efforts of these materials often employ Edisonian trial–and–error tactics with limited molecular– level understanding of the underlying interactions between polymers and drugs. Herein, a rational approach to establish fundamental structure–property relationships is presented using well–defined, modular polymer platforms. Specifically, Chapters 3–5 describes the synthesis, characterization, and performance properties of a multicomponent acrylic polymer, inspired by hydroxypropyl methylcellulose acetate succinate (HPMCAS). By strategically varying the precise monomeric incorporation, microstructure, and chemical character of these HPMCAS analogs, we systematically examined how specific polymeric attributes produce stable, amorphous spray–dried dispersions with various hydrophobic drugs at increasing drug loadings. Chapter 6 extends these ideas for precision drug formulation, a concept that specialized polymers can be judiciously constructed around drugs of high therapeutic interest. High–throughput synthesis and screening tools expedited this process, akin to molecular evolution methods in biology and genetics; in vitro and in vivo results show the remarkable versatility and ability of designer polymers to controllably solubilize drugs. Altogether, this simple but universal approach combining synthetic and predictive ingredients enables the establishment of robust guidelines to meet unfulfilled needs in the pharmaceutical landscape.